Vantage Snippets are short summaries of breaking news stories.
Evaluate Vantage will not publish on Monday May 31 owing to a public holiday in the UK. We will return on June 1, 2021.
The highly secretive biotech Lyell Immunopharma had already raised $493m in the second-biggest private financing of 2020, and yesterday brought news of its plan to float. Lyell hopes to raise at least $150m in the IPO, whose post-money valuation has yet to be set. The group’s pipeline is wholly preclinical, and no IND will even be filed until next year – a fact that might ordinarily restrain enthusiasm. But Lyell is backed by the former chief executive of Juno, Hans Bishop, whose other preclinical biotech, Sana, floated at a valuation of about $4bn. So secretive is Lyell that it was only recently revealed who else was behind the company, and its SEC filing spells out that it appears to be the brainchild of Drs Stan Riddell, formerly of Juno, and Crystal Mackall, ex-NCI – both highly prominent Car-T pioneers. Another Juno/NCI veteran, Rick Klausner, was until recently chief executive, for which he was paid $38.9m in 2020, but last August Liz Homans, formerly of Roche, took over that role. The filing also reveals Lyell’s pipeline to be a mix of Car-T, engineered TCR and TIL approaches, which scientifically tend not to make happy bedfellows.
|Lyell's pipeline (all projects preclinical)|
|LYL797||Anti-Ror1 Car-T||Ex vivo reprogrammed to overcome T-cell exhaustion and impart durable stemness||Juno/Hutch had been developing an anti-Ror1 Car-T therapy, JCAR024, apparently based on the same rabbit-derived binder|
|LYL845||Polyclonal TILs||Ex vivo reprogrammed to impart durable stemness||Targeting solid tumour use|
|NY-ESO-1c259||Anti-NY-ESO-1 eTCR||Ex vivo reprogrammed to overcome T-cell exhaustion or impart durable stemness||Partnered with Glaxosmithkline, for synovial sarcoma and other uses|
|Source: SEC document.|
With Vectura’s sale to the private equity company Carlyle Group for £958m ($1.4bn), UK investors have another reason to be down on biotech. Vectura, like Cenes and Vernalis before it, is the result of numerous UK biotech mergers that failed to amount to much. During its 24-year existence Vectura subsumed Innovata, Activaero and Skyepharma for a combined £680m, but shortly after building this respiratory disease focus it gave up on drug development to become a service company. Its sale price amounts to a 142% premium to its 2004 IPO. Cenes and Vernalis were sold for a pittance to Paion and Ligand respectively, and UK biotech’s shining star is probably GW Pharmaceuticals, which had to seek fame and fortune in the US. The UK still produces cutting-edge science, but the likes of Autolus, Achilles and Nightstar all chose Nasdaq to float. The UK sector is left with a rump of micro caps, and even the once mighty Oxford Biomedica is now largely a services business. Though Vectura has started generating contract revenue its top line is driven by Flutiform, Enerzair Breezhaler and an Advair generic, and a private equity group would typically now cut costs and take on debt.
|A potted history of Vectura|
|1997||Company is founded|
|2004||Lists on London's Aim at 56 pence per share|
|2007||Acquires Innovata for £131m in stock|
|2014||Acquires Activaero for £108m in cash and stock|
|2016||Acquires Skyepharma for £441m in stock|
|2020||Management overhaul and change of focus from respiratory drug development to contract work and manufacturing|
|2020/21||Patent win results in £128m payout from Glaxosmithkline|
|2021||Company is sold to Carlyle Group for £958m (136 pence per share + 19 pence dividend)|
|Source: company filings.|
Restricting Keytruda’s front-line oesophageal cancer label to ≥10% PD-L1 expressers, as the EU is proposing to do, makes perfect sense given the available data. This would put the regulator, whose CHMP recommendation was revealed yesterday, at odds with the US FDA, which in March approved Merck & Co’s drug in this cancer in all-comers. At issue is the supporting study, Keynote-590, in first-line oesophageal/gastroesophageal junction carcinoma (Esmo 2020 – double win complicates the gastric cancer picture, September 21, 2020). This showed a survival benefit in ≥10% PD-L1 expressers and in all-comers. But subgroup data presented at Esmo suggested that an exceptionally strong result in PD-L1 expressers drove the all-comers result: in subjects expressing PD-L1 at below 10% the confidence interval’s upper bound for overall survival was above 1.00, meaning that some patients might have been better off on chemo alone. While it is possible that many 1-10% PD-L1 expressers did derive a benefit, the CHMP is – not for the first time – proposing a tougher line than the FDA. And for doctors the gastroesophageal cancer space is further complicated by the recent US approval of Keytruda plus Herceptin in Her2-positive patients, and by that of adjuvant Opdivo.
The latest cut of a prostate cancer cohort from Exelixis’s Cosmic-021 trial of Cabometyx plus Tecentriq show a deteriorating dataset, but this is just one of the group’s problems. The second is the upcoming results of Novartis’s Vision study of 177Lu-PSMA-617 in a similar setting; Vision data are under wraps until next month’s Asco meeting, but their selection as a late-breaker hints at a good result. A strong Vision readout would undermine Exelixis’s case for accelerated Cabometyx approval based on Cosmic-021 – even before considering the latter dataset’s deterioration. Exelixis plans a filing in high-risk mCRPC patients progressed on Zytiga or Extandi, but yesterday said an independent review of Cosmic-021 showed overall remission rate of just 18%, which Stifel reckons is not far off what PD-(L)1 blockade alone can do. At Asco-GU in February 2020 Exelixis had boasted a 33% response rate – in a smaller dataset and according to more lenient, investigator review. True, Novartis’s Vision trial gives 177Lu-PSMA-617 on top of Zytiga/Xtandi, but this technical difference will unlikely amount to much if Vision establishes ’617 as a new late-line standard. Evaluate Pharma sellside consensus sees Cabometyx generating $106m of 2026 revenues in prostate cancer, versus $552m for ’617.
|High-risk, post-Zytiga/Xtandi patients in Cosmic-021|
|Data point||Median follow-up||n||ORR||CR|
|Asco-GU, Feb 2020||12.6mth||36||33%||2|
|Source: Exelixis; *by blinded independent review.|
Swift approval for amivantamab, now trademarked Rybrevant, gives J&J first crack at non-small cell lung cancer driven by exon 20 insertions, a hard-to-treat subset. The accelerated approval comes two months before the FDA’s goal, and was based on data presented at World Lung earlier this year that included a 40% response rate. Developers have previously struggled to hit this mutation effectively with small molecules; Rybrevant is notable for being a bispecific against EGFR and Met. Rybrevant’s infused administration could become a hindrance, a theory that might be tested should Takeda’s small molecule mobocertinib win approval by its October 26 Pdufa date. Mobocertinib data at World Lung were arguably less impressive than Rybrevant’s, although the evidence for both is likely to evolve. Spectrum seems to have restricted its work with poziotinib to Her2 exon 20 mutations, which would not make it a direct competitor. Otherwise the pipeline includes a couple of projects in development in China, and BDTX-189 from Black Diamond, which underwhelmed last week with data due to be presented at Asco next month. Cullinan is also presenting an update, on CLN-081, at the conference.
|Notable ongoing studies in EGFR/Her2 exon 20 mutations|
|Project||Mechanism||Sponsor/Collaborators||Trial name/NCT ID||Trial description|
|Rybrevant||EGFR-Met bispecific antibody||J&J||Papillon||Ph3 1st-line confirmatory study|
|J&J||Chrysalis||Ph1 with exon 20 cohort in relapsed NSCLC|
||EGFR/Her2 exon 20 kinase inhibitor||Takeda||NCT04129502||Ph3 1st-line study|
|Takeda||NCT02716116||Ph1/2; 1st and 2nd-line NSCLC with EGFR or Her2 exon 20|
|Poziotinib||EGFR/Her2 exon 20 kinase inhibitor||Spectrum||Zenith20||Ph2 (open label); 1st and 2nd line study|
|BDTX-189||TKI targeting all EGFR/Her2 mutations||Black Diamond Therapeutics||MasterKey-01||Ph1 trial with cohorts of several EGFR or Her mutations; data at Asco|
|JMT101||Anti-EGFR MAb||Shanghai JMT-Bio||NCT04448379||Phase 1b in exon 20|
|CLN-081||EGFR exon 20 kinase inhibitor||Cullinan Oncology||NCT04036682||Ph1/2 in EGFR exon 20; data at Asco|
|DZD9008||EGFR/Her2 exon 20 kinase inhibitor||Dizal Pharmaceuticals||NCT03974022||Ph1/2 in EGFR exon 20/Her2 mutations|
|Tarloxotinib bromide||Pan-ErbB inhibitor||Rain Therapeutics||NCT03805841||Ph2; exon 20 Her2-activating mutations, other NRG1/ERBB gene fusions; asset possibly deprioritised|
|Source: clinicaltrials.gov & Evaluate Pharma.|
Despite NGM Bio’s trial of aldafermin in Nash hitting some secondary endpoints the company has decided not to push on with the programme, saying it will not be ploughing cash into another study. The phase 2b Alpine 2/3 study, in patients with stage 2/3 fibrosis, failed to meet the primary endpoint, fibrosis improvement by at least one stage with no worsening of Nash, with aldafermin versus placebo. The company's shares plummeted 40% in early trading. Alpine 4, in patients with very advanced fibrosis and compensated cirrhosis, will continue, and NGM has an option to jump on board with MK-3655, an insulin sensitiser out-licensed to Merck & Co; effectively, however, one of the investment community's most closely-followed Nash plays looks to have thrown in the towel in this disease. Several other companies are looking at fibroblast growth factors, but the news is another reminder that Nash is an incredibly tough target, despite a huge amount of hope, and hype, in the past few years. NGM's attention will now turn to its remaining pipeline, which includes NGM621 in phase 2 in geographic atrophy. The project is an anti-complement C3 antibody, much like Apellis’s intravitreal pegcetacoplan, which is due to report phase 3 data in the third quarter.
|Phase 2 fibroblast growth factors for Nash|
|Product||Company||Mechanism of Action||Note|
|Pegbelfermin (BMS-986036)||Bristol-Myers Squibb/Ambrx||FGF21 stimulant||Falcon 1 and 2 studies had primary completion dates in Sept 2020|
|Aldafermin||NGM||FGF19 analog||Alpine 2/3 study failed, Alpine 4 ongoing PC June 22|
|Efruxifermin (AKR-001)||Amgen/Akero||FGF21 stimulant||Two parallel Ph2b in fibrosis stage 2/3 (Harmony) and F4 to start this year, data Q3 2022|
|MK-3655 (NGM313)||Merck/NGM||FGFR1c antibody||Ph2b (fibrosis stage 2/3) PC 2023|
|BIO89-100||89bio||FGF21 stimulant||Ph2b Enliven expected to start Q2 (fibrosis stage 2/3)|
|Source: Evaluate Pharma, clinicaltrials.gov|
Lilly will submit its dual GIP/GLP-1 agonist tirzepatide to regulators by the end of 2021 after the project scored today in its fifth pivotal trial, Surpass-4. The study, in type 2 diabetes patients with increased cardiovascular risk, found tirzepatide was superior to insulin glargine on HbA1c and weight loss. More importantly, it helped demonstrate tirzepatide’s cardiovascular safety, a requirement for type 2 diabetes drugs. A meta-analysis of the Surpass programme found a 19% relative risk reduction in major cardiovascular events with tirzepatide versus pooled comparator data; Surpass-4 accounted for the majority of these events. The go-to dose of tirzepatide will be 5mg, Lilly’s chief scientific officer, Daniel Skovronsky, said during the group’s first-quarter call, with the option to dose higher. If approved, tirzepatide will become the latest weapon in Lilly’s battle with Novo Nordisk in diabetes; the Danish group ditched a glucagon/GLP-1 co-agonist and a glucagon, GLP-1 and GIP tri-agonist last year, citing toxicity concerns. Lilly has its own tri-agonist, “triple G”, which it has said could be even better than tirzepatide. Phase 1 data with this project, as well as results from Surpass-1, 2, 3 and 5, will feature at next month’s ADA meeting.
|Surpassing expectations? The tirzepatide data so far|
|Trial name/ID||Trial details||Data (5mg dose)*||Timing|
|Surpass-1||vs placebo in uncontrolled T2DM||A1c -1.75%; weight loss 6.3kg||Hit Dec 2020|
|Surpass-2||vs Ozempic + metformin in T2DM||A1c -2.01%; weight loss 7.6kg||Hit Mar 2021|
|Surpass-3||vs Tresiba in T2DM||A1c -1.85%; weight loss 7.0kg||Hit Feb 2021|
|Surpass-4||vs insulin glargine in pts with T2DM & increased CV risk||A1c -2.11%; weight loss 6.4kg||Hit May 2021|
|Surpass-5||vs placebo in T2D inadequately controlled with insulin glargine +/- metformin||A1c -2.11%; weight loss 5.4kg||Hit Feb 2021|
|Surpass-6||vs Humalog in T2DM inadequately controlled with insulin glargine +/- metformin||-||Completes Aug 2022|
|Surpass-CVOT||vs Trulicity on major CV events in T2DM pts||-||Completes Oct 2024|
|*Treatment-regimen estimand. Source: Lilly releases.|
Merus has managed to do what many others have not: show activity in pancreatic cancer. It did this by looking specifically at a genetic mutation: its lead bispecific, zenocutuzumab, produced a 40% overall response rate among 10 pancreatic patients with NRG1 fusions, an Asco abstract revealed. However, performance in other cancer types was less impressive. The analysis, of the phase 1/2 Enrgy trial plus an early-access programme, also included 18 patients with NSCLC and five with other solid tumours; across all 33 the ORR was 27% at a January 12 data cut-off. Merus, whose stock fell 5% this morning, will hope that the pancreatic result holds up – and perhaps for an improvement in other tumour types – when updated results are presented at Asco on June 4. The NRG1 fusion niche is small, with only around 1% of solid tumours thought to carry this mutation, but not many others are currently looking at this space. Merus’s main rival is Elevation Oncology, which is developing seribantumab, an asset Merrimack abandoned after its failure in NSCLC. Boehringer’s approved NSCLC drug Gilotrif has also shown evidence of a benefit in NRG1 fusion-positive patients, and is being investigated in the Asco-sponsored Tapur umbrella trial.
|Selected projects targeting NRG1 fusion mutations|
|Merus||Zenocutuzumab (MCLA-128)||Her2/Her3-targeting bispecific||Pancreatic, NSCLC, other solid tumours||Ph1/2 Enrgy & early access programme presented at Asco 2021|
|Elevation Oncology||Seribantumab (MM-121)||Anti-Her3 monoclonal antibody||Various solid tumours inc. pancreatic & lung||Ph2 Crestone completes Jun 2022|
|Rain Therapeutics||Tarloxotinib||Pan-ErbB inhibitor||NSCLC & other solid tumours||Ph2 completed Mar 2021; project appears to be deprioritised|
|Boehringer Ingelheim||Gilotrif||Pan-ErbB inhibitor||Approved for EGFR-mutated NSCLC||Asco-sponsored Tapur includes Gilotrif/NRG1 arm|
|Hummingbird Bioscience||HMBD-001||Anti-Her3 monoclonal antibody||Various solid tumours||Preclinical|
|Source: Evaluate Pharma & clinicaltrials.gov.|
Last October Iovance pushed back the filing of its lead project, lifileucel, in metastatic melanoma from 2020 to 2021. Now the company has been delayed again, and does not expect to be able to submit the project to the FDA until the first half of next year. Standardising the autologous tumour-infiltrating lymphocyte therapy still appears to be the problem, with the FDA apparently unsatisfied with the company’s latest potency assay data. Work on these assays will continue, and lifileucel’s launch is now unlikely until 2023, Stifel analysts noted. Iovance is also trialling the project in cervical cancer, where the pivotal C-145-04 study is enrolling. Iovance’s latest delay might allow some of its rivals to catch up: since Evaluate Vantage last carried out this analysis several more TIL players have emerged, including Instil Bio, which recently pulled off a $368m IPO. Instil is developing both unmodified and genetically engineered TILs; Intima Bioscience and KSQ Therapeutics are working on Crispr-edited TILs. Iovance stock slipped 11% in early trade, with the company providing a cautionary tale to the rest of the space, by highlighting that, for cell therapies, generating clinical data is just part of the equation.
|Selected TIL approaches in development|
|Company||Lead TIL project||Status||Note|
|Iovance Biotherapeutics||Lifileucel||Melanoma filing delayed until H1 2022; cervical cancer ph2 ongoing||First cut of Keytruda combo data from cohort A, checkpoint-inhibitor naive melanoma, at Asco|
|Immatics||IMA101/Actolog||Ph1 in solid tumours||Data presented at SITC 2020; company appears to have deprioritised|
|Achilles Therapeutics||ATL001||Ph1/2 in NSCLC (Chiron) & melanoma (Thetis)||Chiron interim data due H2 2021|
|Intima Bioscience||Crispr-engineered TILs||Ph1/2 in GI cancers||Crispr edited to inhibit CISH|
|Instil Bio||ITIL-168||Ph2 in melanoma to start H2 2021 (compassionate use data proxy for ph1)||Unmodified TILs|
|Nurix Therapeutics||DETIL-0255||Ph1 to start H2 2021||Uses ex vivo CBL-B inhibition|
|KSQ Therapeutics||KSQ-001||IND-enabling studies ongoing||Crispr edited to inhibit CT-1|
|Obsidian Therapeutics||cytoTIL15||IND-enabling studies ongoing||Engineered with membrane-bound IL15|
|Adaptimmune||TIL-IL7||Preclinical||TILs co-expressing IL-7; collaboration with CCIT, Denmark|
|Source: Evaluate Pharma & clinicaltrials.gov.|
The table in this story has been updated to remove Genocea's GEN-011.